Academic literature on the topic 'Autoimmune Polyendocrine Syndrome type-1 (APS-1)'

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is characterised by multiple autoimmune endocrinopathies and results from mutations in the AIRE (autoimmune regulator) gene. Approximately 80% of patients present with hypoparathyroidism which is suggested to result from autoimmune responses against the parathyroid glands. The calcium-sensing receptor (CaSR), which plays a pivotal role in maintaining calcium homeostasis by sensing blood calcium levels and regulating release of parathyroid hormone, has been identified as a parathyroid autoantibody target in APS1. Aims: The main aims of this study were to characterise APS1 patient anti-CaSR autoantibodies in relation to their prevalence, disease associations, epitopes, specificity, IgG subclass and effects upon CaSR function, and to develop an ELISA to detect CaSR autoantibodies in patient sera. Methodology: Immunoprecipitation; radioligand binding assays; phage-display; ELISA; bioassays; protein expression. Results: Autoantibodies against the CaSR were detected in 16 out of 44 (36%) APS1 patients and in none of 38 healthy control subjects (P = < 0.0001). No statistically significant associations were found between the presence of CaSR autoantibodies and the disease manifestations of APS1 including hypoparathyroidism. The detection of CaSR autoantibodies had a specificity of 83%, and a sensitivity of 39% for the diagnosis of hypoparathyroidism. There were no significant associations between the presence of CaSR antibodies and either sex, age or disease presentation age. However, a significant association between a shorter APS1 duration (< 10 years) and positivity for CaSR autoantibodies was noted (P = 0.019). CaSR autoantibody epitopes were identified between amino acids 41-69, 114-126, 171-195 and 260-340 in the extracellular domain of the receptor. Autoantibodies against CaSR epitopes 41-69, 171-195 and 260-340 were exclusively of the IgG1 subclass. Autoantibody responses against CaSR epitope 114-126 were predominantly of the IgG1 with a minority of the IgG3 subclass. CaSR autoantibodies were analysed for their ability to increase Ca2+-dependent inositol phosphate accumulation in HEK293 cells expressing the CaSR. The results indicated that 4/16 (25%) APS1 patients had anti-CaSR-activating autoantibodies, suggesting that although the majority of APS1 patients do not have CaSR-stimulating autoantibodies, there may be a small minority of patients in whom the hypoparathyroid state is the result of functional suppression of the parathyroid glands. As part of this study, an ELISA was developed using the extracellular domain of the CaSR expressed in Escherichia coli as the antibody-capture antigen. Although this assay was able to detect the presence of autoantibodies in APS1 patient sera, the experimental method still requires further optimisations in order to attain a validated and robust ELISA, as this was not achievable during the present study. Conclusion: The study provides a detailed analysis of the characteristics of CaSR autoantibodies in APS1 patients, although further investigations are required to determine the exact role played by the autoimmune response against the CaSR in the pathogenesis of APS1.

La polyendocrinopathie auto-immune de type 1 (PEA1) est liée aux mutations du gène AIRE. En l’absence de AIRE se développe un défaut de tolérance immune centrale, à l’origine de pathologies auto-immunes multiples spécifiques d’organe. Notre objectif était d’évaluer l’effet d’une altération« exemplaire » du répertoire T sur les empreintes auto-réactives humorales. Les données cliniques etimmunologiques ont été recueillies chez des patients atteints de PEA1, qui ont bénéficié du séquençage du gène AIRE. Chez ces patients ont été analysés les profils d’auto-réactivité sérique IgGet IgM vis à vis des tissus pancréatique et surrénalien, en comparaison à des patients atteints d’autres endocrinopathies auto-immunes, et à des sujets sains. Les bandes antigéniques discriminantes ont été sélectionnées grâce à un test de Chi-2, et une approche immuno-protéomique a permis leur caractérisation moléculaire. Dix-neuf patients atteints de PEA1 ont pu être étudiés. Ils présentaient de1 à 10 manifestations cliniques liées à la maladie. Quatre mutations du gène AIRE différentes ont été identifiées, et la délétion 13-bp dans l’ exon 8 (c.967-979del13) s’est avérée la plus fréquente. L’étude en immuno-empreinte a permis d’identifier 6 antigènes préférentiellement reconnus par les patients atteints de PEA1. Leur caractérisation par approche immuno-protéomique a montré qu’il s’agissait à lafois d’antigènes tissus-spécifiques (lipase pancréatique reconnue à la fois par les IgM et les IgG,amylase pancréatique reconnue par les IgG, Regenerating Protein 1 alpha pancréatique ciblée par lesIgM) mais également ubiquitaires (péroxiredoxine-2 reconnue à la fois par les IgG et les IgM, HeatShock cognate 71kDa Protein ciblée par les IgM, aldose réductase reconnue par les IgG). Ainsi, une altération majeure du répertoire T auto-réactif, telle que celle liée aux mutations du gène AIRE, affecte de manière importante les réponses humorales auto-réactives dépendantes d’ IgG, mais également d’IgM. Ces modifications touchent à la fois des antigènes tissu-spécifiques et ubiquitaires, nous faisant évoquer un rôle au moins partiel de AIRE dans des phénomènes T-indépendants et /ou des altérations de l’immunité naturelle<br>Autoimmune polyendocrine syndrome type 1 (APS1) is caused by mutations in the AIRE gene thatinduce central tolerance breakdown which results in tissue-specific autoimmune diseases. Ourobjective was to evaluate the effect of a well-defined T cell repertoire impairment on humoralsystemic self-reactive footprints. Clinical and immunological data were collected, and pathologicalmutations in the AIRE gene were identified by DNA sequencing. Comparative serum self-IgG andself-IgM reactivities, directed towards pancreatic and adrenal protein extracts, of APS1 patients,patients suffering from other autoimmune endocrinopathies and healthy subjects, were tested using Western blotting. Discriminant protein bands were selected using the Chi-square test and molecularcharacterization of these bands was conducted using a proteomic approach. Nineteen patients wereidentified with APS1. Clinical manifestations varied greatly, showing 1 to 10 components. Fourdifferent AIRE gene mutations were identified, and the 13-bp deletion in exon 8 (c.967-979del13) wasthe most prevalent. A singular distortion of seric self-IgG and self-IgM repertoires was noted in APS1patients. IgG and IgM antibodies recognized significantly one tissue-specific (pancreatictriacylglycerol lipase) and one ubiquitous antigens (peroxiredoxin-2). IgM recognized one tissuespecific (Pancreatic regenerating protein 1!) and one ubiquitous antigen (Heat Shock cognate 71kDaProtein). IgG also recognized one tissue-specific (pancreatic amylase) and one ubiquitous antigen(aldose reductase). As expected, a well-defined self-reactive T cell repertoire impairment affected thetissue-specific self-IgG repertoire but also self-IgM repertoire. Our study also reveals discriminant responses against ubiquitous antigens with IgG and IgM antibodies. Some common discriminantantigenic targets were found for IgG and IgM. All these data suggest that T cell-dependent but also T cell-independent mechanisms are involved in APS1. The potent involvement of complementary events related to potent dysfunction in the innate immune response is discussed

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease, whereas autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal disorder characterized by combinations of organ-specific autoimmune manifestations including hypoparathyroidism and intestinal dysfunction, and may serve as a model for organ-specific autoimmunity. Autoantibodies directed against proteins expressed in the affected tissues are found in both diseases. From a chondrocyte cDNA expression library, we identified the protein AHNAK as an autoantigen in SLE. Anti-AHNAK antibodies were found in 29.5% (18/61) of patients with SLE, 4.6% (5/109) of patients with rheumatoid arthritis, and 1.2% (2/172) of blood donors. Using a candidate approach, we analyzed the prevalence in APS1 and other organ-specific autoimmune diseases, of autoantibodies against the pyridoxal phosphate-dependent enzymes histidine decarboxylase (HDC) and cysteine sulfinic acid decarboxylase (CSAD), which are structurally closely related to known autoantigens. Anti-HDC and anti-CSAD reactivity was detected exclusively in APS1 patient sera. Anti-HDC antibodies were detected in 37.1% (36/97) of the APS1 sera, did not cross-react with aromatic L-amino acid decarboxylase, and were associated with intestinal dysfunction and loss of histamine-producing gastric enterochromaffin-like cells. In contrast, anti-CSAD reactivity was detected in 3.6% (3/83) of APS1 sera and cross-reacted with recombinant glutamic acid decarboxylase. From a parathyroid cDNA expression library, novel spliced transcripts of the CLLD4 gene on human chromosome 13q14, encoding 26 and 31 kDa isoforms recognized by autoantibodies in 3.4% (3/87) of APS1 patients, were identified and found to be preferentially expressed in lung and ovary. Both isoforms contain an N-terminal BTB/POZ domain, similarly to the TNF-alpha-regulated protein B12, localize both to the cytoplasm and nucleus in transfected COS cells, and form oligomers in vitro. The CLLD4 gene is located in a region frequently deleted in several forms of cancer, including lung and ovarian tumors. In conclusion, we have identified and partially characterized AHNAK and HDC as two common targets of autoantibodies in SLE and APS1, respectively. We have also identified CSAD and CLLD4 as two minor autoantigens in APS1, one of which is a novel protein with unknown function.

Research Doctorate - Doctor of Philosophy (PhD)<br>Background: Autoimmune diseases arise from the breakdown of central tolerance resulting in the escape of self reactive T-lymphocytes from the thymus to the periphery. As a group of conditions, autoimmune diseases occur in approximately 5% of the general population and represent the third most common cause of morbidity, placing considerable expenses on the health care system and society. Understanding the underlying pathogenesis and pathophysiology of these diseases is therefore important for the correct diagnosis and treatment of these patients. While some autoimmune diseases have been paid particular attention, little is known about the pathogenesis of the pituitary autoantibodies. Aims: To identify target autoantigens in the pituitary autoimmune disease lymphocytic hypophysitis and autoantigen(s) relating to pituitary manifestations in APS1 patients. Methods: A pituitary cDNA expression library was immunocreened with lymphocytic hypophysitis and APS1 patient sera to identify target autoantigens. These were then tested in an ITT assay for autoantigen specificity to relating to the disorders. Immunofluorescence of pituitary tissue was performed to determine the cell types targeted in the disorders. Results: Two APS1 autoantigens were identified, a major autoantigen ECE-2 and a minor autoantigen TSGA10, although neither apparently correlated to pituitary manifestations in APS1. T-box 19 was also identified as a significant minor autoantigen in 10.5% of lymphocytic hypophysitis patients. Immunoreactivity in a single lymphocytic hypophysitis patient against cells of the intermediate lobe of the guinea pig pituitary is also reported. Discussion: Immunoscreening a target organ cDNA expression library is a valuable method for identifying novel autoantigens, with immunopreciptation assay a quick and reliable method for analysing a large cohort of patients for autoantibodies. We have identified another two APS1 autoantigens and the first significant autoantigen in lymphocytic hypophysitis. While further characterisation of these autoantigens are required, these novel findings broaden our current understanding of pituitary autoimmunity.

Research Doctorate - Doctor of Philosophy (PhD)<br>Background: Autoimmune diseases arise from the breakdown of central tolerance resulting in the escape of self reactive T-lymphocytes from the thymus to the periphery. As a group of conditions, autoimmune diseases occur in approximately 5% of the general population and represent the third most common cause of morbidity, placing considerable expenses on the health care system and society. Understanding the underlying pathogenesis and pathophysiology of these diseases is therefore important for the correct diagnosis and treatment of these patients. While some autoimmune diseases have been paid particular attention, little is known about the pathogenesis of the pituitary autoantibodies. Aims: To identify target autoantigens in the pituitary autoimmune disease lymphocytic hypophysitis and autoantigen(s) relating to pituitary manifestations in APS1 patients. Methods: A pituitary cDNA expression library was immunocreened with lymphocytic hypophysitis and APS1 patient sera to identify target autoantigens. These were then tested in an ITT assay for autoantigen specificity to relating to the disorders. Immunofluorescence of pituitary tissue was performed to determine the cell types targeted in the disorders. Results: Two APS1 autoantigens were identified, a major autoantigen ECE-2 and a minor autoantigen TSGA10, although neither apparently correlated to pituitary manifestations in APS1. T-box 19 was also identified as a significant minor autoantigen in 10.5% of lymphocytic hypophysitis patients. Immunoreactivity in a single lymphocytic hypophysitis patient against cells of the intermediate lobe of the guinea pig pituitary is also reported. Discussion: Immunoscreening a target organ cDNA expression library is a valuable method for identifying novel autoantigens, with immunopreciptation assay a quick and reliable method for analysing a large cohort of patients for autoantibodies. We have identified another two APS1 autoantigens and the first significant autoantigen in lymphocytic hypophysitis. While further characterisation of these autoantigens are required, these novel findings broaden our current understanding of pituitary autoimmunity.